Additive renoprotective effect of candesartan and tetrahydrobiopterin in rats after 5/6 nephrectomy.

BACKGROUND: Chronic treatment with candesartan cilexetil (C) improves the outcome of rats after 5/6 nephrectomy (Nx). Tetrahydrobiopterin (BH4), an essential cofactor for appropriate endothelial nitric oxide synthase (eNOS) activity, prevents an increase in blood pressure (BP) in Nx rats when given immediately after surgery. In the present study, we evaluated the renoprotective effect of a combined treatment. METHODS: Five groups of rats were studied: SHAM (sham-operated rats, n=12); SNx (untreated 5/6 nephrectomized rats, n=15); C (SNx rats treated with candesartan cilexetil, 5 mg/kg/day per os, n=11); C+BH4 (SNx rats treated with candesartan cilexetil and BH4, 10 mg/kg/day intraperitoneally, n=11); and BH4 (SNx rats treated with BH4, 10 mg/kg/day intraperitoneally, n=11). Treatment began 30 days after surgery, when hypertension and renal insufficiency have developed. This day was considered as day 1 of treatment for statistical comparisons. The study was continued until 50% mortality was achieved in the SNx rats (4 months after surgery). RESULTS: The survival rates were 100% for SHAM, 47% for SNx, 50% for BH4, 64% for C and 80% for C+BH4 (P<0.05 vs all). Untreated Nx rats developed hypertension, proteinuria (UP) and severe renal insufficiency. Mortality was associated with a lower renal function and increased urine protein excretion. In C and C+BH4 rats, systolic blood pressure (SBP) decreased significantly. BH4 alone had a mild non-significant effect on SBP. C and C+BH4 treatments attenuated significantly the increase in proteinuria found in SNx animals. The weight of the remnant kidneys as well as the severity of glomerulosclerosis were significantly lower in the C+BH4 rats. CONCLUSION: This study shows that in subnephrectomized rats, addition of BH4 to a treatment with candesartan had an additive renoprotective effect. The mechanism of such action may include a better control of BP associated with a blockade of actions of angiotensin II (Ag II), an improvement in nitric oxide synthesis and a balanced redox.

Effect of chronic tetrahydrobiopterin supplementation on blood pressure and proteinuria in 5/6 nephrectomized rats.

BACKGROUND: Tetrahydrobiopterin (BH4) is a key cofactor of nitric oxide (NO) synthase. Reduced BH4 levels may mediate endothelial NO synthase uncoupling, resulting in reduced NO synthesis and enhanced oxidative stress. In rats after 5/6 nephrectomy (Nx), administration of BH4 prevents the onset of hypertension, typically observed 10 days after Nx. This effect is associated with an increased synthesis of NO. The aim of the present study was to evaluate the effect of chronic BH4 therapy on blood pressure and renal morphology. METHODS: During an 8 week period, five groups of rats were studied: untreated 5/6 Nx rats, BH4-treated Nx rats (BH4, 10 mg/kg body weight/day administered intraperitoneally), l-arginine treated Nx rats (LA, 130 mg/kg/day), diltiazem-treated Nx rats (DILT, 30 mg/kg/day) and sham-operated rats. Treatments were commenced 24 h after surgery. Systolic blood pressure values (SBP), 24 h proteinuria (UP) and creatinine clearance rate (CCR) were assessed before and at weeks 4 and 8 of the study period. Histological changes in the kidney were evaluated at the end of the study (week 8). RESULTS: Compared with baseline, in Nx rats both SBP and UP increased significantly (112+/-1 to 136+/- 1.4 mmHg, P<0.01 and 23+/-2 to 127 +/- 26 mg/day, P<0.01, respectively). Treatment with BH4 normalized SBP values as did treatment with LA and DILT (109+/-3, 115+/-2 and 114+/-2 mmHg, respectively). UP was markedly reduced by BH4, the reduction being similar to that obtained by LA and significantly more marked than that of DILT rats (20+/-2, 28+/-3 and 62+/- 14 mg/day, respectively). CCR was equally decreased in all Nx groups. Histological evaluation showed the development of mesangial expansion in Nx rats, an effect that was significantly blunted by all treatments. CONCLUSIONS: In rats after 5/6 nephrectomy, BH4 supplementation initiated 24 h after surgery and maintained for 8 weeks preserved SBP, reduced UP and prevented the development of glomerular mesangial expansion.

The "DRIL" procedure--a neglected way to treat the "steal" syndrome of the hemodialysed patient.

BACKGROUND: The ischemic "steal" syndrome complicates angio-access in a growing number of hemodialysed patients. Until now, operative attempts (fistula ligation or banding) to treat this problem have met with only limited success. OBJECTIVE: To assess the results of DRIL (distal revascularization-interval ligation) procedure in treating the "steal" syndrome. METHODS: A retrospective review (1996-2002) was conducted of all 11 patients who underwent the DRIL procedure in two tertiary care hemodialysis units. RESULTS: Two patients were excluded because of inadequate medical documentation. All of the nine patients remaining suffered from overt atherosclerotic disease, six had diabetic nephropathy and four were smokers. The arteriovenous access, which led to the "steal" syndrome, was proximally located in all (antecubital in 8, thigh area in 1). "Steal" symptoms included hand pain, paraesthesia, neurologic deficits and gangrenous ulcers. DRIL was technically successful in all patients. There were no perioperative deaths. Immediate and complete relief of pain was achieved in eight of the nine patients. One patient with gangrene later required a transmetacarpal amputation. No patient required hand amputation. During follow-up (range 1-26 months) hemodialysis was continued uninterruptedly using the problematic AVA in all patients. Thrombosis occurred in the AVA in only two patients after the DRIL procedure at 9 and 24 months postoperatively, respectively. Three patient deaths were unrelated to the DRIL. CONCLUSIONS: In selected patients the DRIL procedure is a safe and effective way to treat the "steal" syndrome. AVA patency is not compromised by this operation. Preoperative angiography, before and after manual compression of the AVA, is crucial for the proper selection of patients who will benefit most from the DRIL procedure.

Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide.

BACKGROUND: Nitric oxide inactivation by superoxide impairs endothelium-dependent vasodilation and plays a role in various forms of hypertension. Almost no data exist regarding hypertension secondary to chronic renal failure. Previous studies have shown that endothelium-related relaxations, secondary to decreased nitric oxide bioactivity, are impaired in resistance vessels from rats 3 to 10 days after renal mass reduction (RMR). METHODS: The membrane-permeable superoxide dismutase (SOD)-mimetic (tempol) was administered IP (1.5 mmol/kg/day for 10 days) to RMR rats and sham-operated controls (SN). Systolic blood pressure (SBP) was measured by tail cuff manometry at days 0, 3, 6 and 10. The increase of flow induced by acetylcholine (10-6 mol/L) was measured in isolated perfused mesenteric arteries from RMR and SN rats pre-contracted with noradrenaline (1 to 5 micromol/L), with or without exogenous SOD. Plasma levels of advanced oxidative protein products (AOPPs; chloramine-T equivalents) were measured in SN and RMR rats. RESULTS: Tempol prevented the increase of SBP: 118 +/- 2.2 mm Hg at baseline and 122 +/- 1.6 mm Hg at 10 days in tempol-treated vs 118.14 +/- 1.65 mm Hg at baseline and 145 +/- 7.69 mm Hg at 10 days in untreated RMR rats (P < 0.01). Responsiveness to acetylcholine was reduced in RMR rats (peak flow increase: 139 +/- 7.8% vs. 176 +/- 11% in SN, P=0.028 at 3 days and 140 +/- 6.4% vs. 187 +/- 16.9% in SN at 10 days, P=0.007). In arteries pre-incubated with SOD (200 U/mL) the peak flows were 175 +/- 9.4% at 3 days and 157 +/- 5.8% at 10 days (P=0.007 and P=0.051, respectively, vs. control RMR vessels). AOPP values were significantly increased in plasma from RMR rats 3 days after 5/6 nephrectomy (747 +/- 107 vs. 481 +/- 77 micromol/L, P < 0.05) but returned to normal by day 10. AOPP levels were not significantly reduced by tempol. CONCLUSIONS: Increased vascular superoxide production plays a central role in the development of vascular endothelial dysfunction and hypertension early after 5/6 nephrectomy.